Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus

Trent Kunkle, Sanofar Abdeen, Nilshad Salim, Anne Marie Ray, McKayla Stevens, Andrew J. Ambrose, José Victorino, Yangshin Park, Quyen Q. Hoang, Eli Chapman, Steven M. Johnson

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3 Scopus citations

Abstract

We recently reported the identification of a GroEL/ES inhibitor (1, N-(4-(benzo[d]thiazol-2-ylthio)-3-chlorophenyl)-3,5-dibromo-2-hydroxybenzamide) that exhibited in vitro antibacterial effects against Staphylococcus aureus comparable to vancomycin, an antibiotic of last resort. To follow up, we have synthesized 43 compound 1 analogs to determine the most effective functional groups of the scaffold for inhibiting GroEL/ES and killing bacteria. Our results identified that the benzothiazole and hydroxyl groups are important for inhibiting GroEL/ES-mediated folding functions, with the hydroxyl essential for antibacterial effects. Several analogs exhibited >50-fold selectivity indices between antibacterial efficacy and cytotoxicity to human liver and kidney cells in cell culture. We found that MRSA was not able to easily generate acute resistance to lead inhibitors in a gain-of-resistance assay and that lead inhibitors were able to permeate through established S. aureus biofilms and maintain their bactericidal effects.

Original languageEnglish (US)
Pages (from-to)10651-10664
Number of pages14
JournalJournal of Medicinal Chemistry
Volume61
Issue number23
DOIs
StatePublished - Dec 13 2018

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Kunkle, T., Abdeen, S., Salim, N., Ray, A. M., Stevens, M., Ambrose, A. J., Victorino, J., Park, Y., Hoang, Q. Q., Chapman, E., & Johnson, S. M. (2018). Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus. Journal of Medicinal Chemistry, 61(23), 10651-10664. https://doi.org/10.1021/acs.jmedchem.8b01293